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Date of Award
CHAPTER 1: Multidrug-resistant bacteria is a threat to public health and there is a need for the development of new antibiotics to fight bacterial resistance. Aminoglycoside antibiotics are attractive to researchers due to their lack of known drug related allergies, low cost, and broad spectrum of activity; however, they can cause nephrotoxicity and ototoxicity in patients. We modified the 2-deoxystreptamine ring of paromomycin to make the drug more flexible and potentially more selective for the bacterial ribosomal A-site to circumvent off-target effects that cause ototoxicity. However, we found that our compound, paromomexin, was significantly less active than paromomycin in all assays. Future 2-deoxystreptamine mimics will provide structural rigidity while allowing greater flexibility of the amines for binding in the A-site.
CHAPTER 2: Glycans play an important role in the function of healthy cells. The regulation of O-mannosylation and sialic acid capping on glycan chains play key roles in disease and immune response pathways, of which we know surprisingly little. A current challenge is a lack of sensitive biochemical and chemoproteomic tools to identify these modifications. Using metabolic labeling techniques, we gathered preliminary data on O-mannosylation in vitro and glycan capping responses to inflammation in vivo. In the future, we plan to use mannose metabolic labeling tools to evaluate O-mannosylation in breast cancer cells and sialic acid glycosylation in response to toxicant exposure in pregnant mice.
CHAPTER 3: O-GlcNAcylation is a highly dynamic post-translational modification that is imperative to the function and health of cells. There has been a substantial amount of research done to investigate this modification and how it impacts various disease states; however, the tools currently available to track O-GlcNAcylation can only reveal the modifications made after the OGT/OGA cycle has reached homeostasis. We developed photo-controllable GlcNAc analogs to access timepoints that are currently unavailable to researchers before the OGT/OGA cycle becomes homeostatic. We were able to observe protein modification at timepoints as low as 10 minutes; however, problems with the tools in biological systems persist and are still undergoing optimization. In the future, we plan to continue optimization of our current tools and develop several new analogs for testing in biological systems.
Kondor, Courtney, "Development Of Carbohydrate-Based Antibiotics And Metabolic Chemical Reporters" (2022). Wayne State University Dissertations. 3677.